Functional involvement of γ-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2)

Journal of Neuroinflammation
Konstantin GlebovJochen Walter

Abstract

Triggering receptor expressed on myeloid cells-2 (TREM2) exerts important functions in the regulation of monocytes, like dendritic cells, osteoclasts, tissue macrophages, and microglia. Mutations in TREM2 are associated with several diseases, including Nasu-Hakola disease, frontotemporal dementia, and Alzheimer's disease (AD). TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis. We show that inhibition of γ-secretase-dependent cleavage of the TREM2 C-terminal fragment in cellular membranes interferes with TREM2-dependent signaling and cellular function. Inhibition of γ-secretase decreases membrane-proximal signaling and intracellular Ca(2+) response. Decreased signaling alters morphological changes and phagocytic activity of cells upon selective stimulation of TREM2. The data demonstrate the importance of γ-secretase-dependent intramembrane processing in TREM2-mediated signaling and, thus, a functional relation of two AD-associated proteins.

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Citations

Sep 25, 2017·Journal of Neurochemistry·Jochen WalterKonstantin Glebov
Oct 29, 2017·Biochemical Society Transactions·Aonghus J McCarthyJustin V McCarthy
Mar 3, 2019·Cells·Naoto Oikawa, Jochen Walter
Aug 5, 2017·Molecular Neurodegeneration·Taylor R JayGary E Landreth
Mar 2, 2019·The Journal of Experimental Medicine·Torben MentrupBernd Schröder
Sep 30, 2018·Nature Reviews. Neurology·Tyler K Ulland, Marco Colonna
May 2, 2020·Life Science Alliance·Esteban GutierrezJochen Walter
Jul 9, 2020·Journal of Neuroinflammation·Jiaolong YangZhentao Zhang
Jun 4, 2017·Der Nervenarzt·I KaracaA Ramirez
Apr 4, 2018·Experimental & Molecular Medicine·Yingjun ZhaoHuaxi Xu
Mar 5, 2021·The Journal of Biological Chemistry·Frédéric CheclerInger Lauritzen
Sep 16, 2021·FEBS Open Bio·Yuumi OkuzonoShuji Sato

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Methods Mentioned

BETA
transgenic
light microscopy
fluorescence microscopy
glycosylation

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